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Septal Contributions to Olfactory Bulb Interneuron Diversity in the Embryonic Mouse Telencephalon: Role of the Homeobox Gene Gsx2 Shenyue Qin1,2, Stephanie M

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Septal Contributions to Olfactory Bulb Interneuron Diversity in the Embryonic Mouse Telencephalon: Role of the Homeobox Gene Gsx2 Shenyue Qin1,2, Stephanie M Qin et al. Neural Development (2017) 12:13 DOI 10.1186/s13064-017-0090-5 RESEARCH ARTICLE Open Access Septal contributions to olfactory bulb interneuron diversity in the embryonic mouse telencephalon: role of the homeobox gene Gsx2 Shenyue Qin1,2, Stephanie M. Ware5, Ronald R. Waclaw1,4 and Kenneth Campbell1,3* Abstract Background: Olfactory bulb (OB) interneurons are known to represent diverse neuronal subtypes, which are thought to originate from a number of telencephalic regions including the embryonic dorsal lateral ganglionic eminence (dLGE) and septum. These cells migrate rostrally toward the OB, where they then radially migrate to populate different OB layers including the granule cell layer (GCL) and the outer glomerular layer (GL). Although previous studies have attempted to investigate regional contributions to OB interneuron diversity, few genetic tools have been used to address this question at embryonic time points when the earliest populations are specified. Methods: In this study, we utilized Zic3-lacZ and Gsx2e-CIE transgenic mice as genetic fate-mapping tools to study OB interneuron contributions derived from septum and LGE, respectively. Moreover, to address the regional (i.e. septal) requirements of the homeobox gene Gsx2 for OB interneuron diversity, we conditionally inactivated Gsx2 in the septum, leaving it largely intact in the dLGE, by recombining the Gsx2 floxed allele using Olig2Cre/+ mice. Results: Our fate mapping studies demonstrated that the dLGE and septum gave rise to OB interneuron subtypes differently. Notably, the embryonic septum was found to give rise largely to the calretinin+ (CR+) GL subtype, while the dLGE was more diverse, generating all major GL subpopulations as well as many GCL interneurons. Moreover, Gsx2 conditional mutants (cKOs), with septum but not dLGE recombination, showed impaired generation of CR+ interneurons within the OB GL. These Gsx2 cKOs exhibited reduced proliferation within the septal subventricular zone (SVZ), which correlated well with the reduced number of CR+ interneurons observed. Conclusions: Our findings indicate that the septum and LGE contribute differently to OB interneuron diversity. While the dLGE provides a wide range of OB interneuron subtypes, the septum is more restricted in its contribution to the CR+ subtype. Gsx2 is required in septal progenitors for the correct expansion of SVZ progenitors specified toward the CR+ subtype. Finally, the septum has been suggested to be the exclusive source of CR+ interneurons in postnatal studies. Our results here demonstrate that dLGE progenitors in the embryo also contribute to this OB neuronal subtype. Keywords: Neurogenesis, Neuronal specification, Olfactory bulb, Septum, Transcription factor * Correspondence: [email protected] 1Divisions of Developmental Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA 3Neurosurgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA Full list of author information is available at the end of the article © The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Qin et al. Neural Development (2017) 12:13 Page 2 of 14 Background LGE and septum, is essential for the normal generation Olfactory bulb (OB) interneurons represent a highly of CR+ and parvalbumin+ OB interneurons [20, 21]. An- diverse neuronal population that serve as important other zinc finger transcription factor Tshz1 is required components in the relay of olfactory signals from the en- for the normal generation of CB+ interneurons as well as vironment to the brain [1]. They are largely inhibitory the radial migration of multiple subtypes after neuro- and modulate local projection neuron activity by blasts ultimately reach the OB [22]. Finally, the TH+ releasing gamma-aminobutyric acid (GABA) [2, 3]. The subpopulation requires both Pax6 and Er81 (Etv1) for complex functions of OB interneurons are accomplished their normal generation [2, 23, 24, 25, 26]. While these by their high diversity, which, at least in part, can be transcriptional regulators are expressed in the migrating recognized as subtypes based on distinct biochemical and differentiating neuroblasts, the homeobox gene markers being expressed [3, 4]. In addition, OB inter- Gsx2 is highly expressed by progenitor cells in the LGE neurons occupy distinct layers of the OB, allowing them and septum, and has been shown to be critical for the to exert their functions through building connections normal generation of many OB interneuron subtypes selectively with tufted cells or mitral cells, the major [20, 27, 28, 29, 30, 31, 32]. Specifically, it was demon- projection neurons in the OB [5, 6, 7]. Interestingly, OB strated that the generation of OB interneurons is se- interneurons of different subtypes show varied prefer- verely compromised when Gsx2 is absent in the dorsal ences in layer localization and neuronal connectivity [3]. LGE (dLGE) [31]. Gsx2 is also highly enriched in the VZ For example, tyrosine hydroxylase-labeled (TH+) progenitor cells of the septum, which represents another dopaminergic interneurons and calbindin+ (CB+)in- important source of OB interneurons at perinatal time terneurons are enriched in the glomerular layer (GL), points [2, 7, 9, 10, 14, 33]. Gsx2 is required for normal whereas calretinin+ (CR+) interneurons are found in gene expression in the embryonic septum, including its both GL and granule cell layer (GCL). The specific downstream effector Ascl1 and related targets [34]. roles of the diverse OB interneuron subtypes in olfac- However, the function of Gsx2 in the specification of tory circuits is not well defined, however, studies have septum-derived OB interneurons has not been shown these interneurons originate from the embry- examined. onic ventral telencephalon and regional progenitor In this study, we utilized two genetic fate-mapping domains in the postnatal SVZ [2, 8, 9, 10]. tools to investigate the LGE and septal contributions to Unlike the locally born projection neurons [11, 12, 13], OB interneuron diversity. In addition, by using a condi- OB interneurons are generated caudal to the bulb within tional knockout strategy, we examined the role of Gsx2 the ventral telencephalon, largely the lateral ganglionic in the generation of septum-derived OB interneurons. eminence (LGE) and septum, from embryonic day 12 Our data demonstrate that the LGE and septum give rise (E12) until birth and subsequently from the postnatal to OB interneuron subtypes differently, with the LGE and adult SVZ, which represents the derivative of these being heterogeneous and the septum providing rather embryonic germinal zones [8, 14, 15, 16]. The newly spe- specifically the CR+ interneurons of the GL. Addition- cified neuroblasts migrate tangentially along the rostral ally, we show that Gsx2 is required for the expansion of migratory stream (RMS) to the OB, where they radially specified septal SVZ progenitors that give rise to CR+ migrate to populate different layers and undergo matur- interneurons. ation [17, 18]. Recently, it has been suggested that OB interneurons of distinct subtypes are produced by Methods progenitor cells in different topological domains of the Animals perinatal telencephalon [2, 7, 9, 10, 16]. For example, Olig2Cre/+ mice [35] and Gsx2e-CIE mice [36] were geno- TH+ interneurons were shown to be generated from the typed with the following primers: JaxCre-5′ (5′-GCGGTC LGE, whereas CR+ interneurons are suggested to be TGGCAGTAAAAACTATC-3′)andJaxCre-3′ (5′-CCAT predominantly produced by the septum [9, 10, 16]. GAGTGAACGAACCTGG-3′). Gsx2flox/+, Gsx2RA/+ and Despite the relatively detailed studies of the origins of Gsx2EGFP/+ alleles were genotyped as previously described OB interneuron subtypes, few genetic approaches have [31, 32]. RosatdTomato (Ai14) mice were genotyped with the been taken to address the contributions of different following primers: Rosa-tdTomato-5′ (5′-GGCATTAAAG- progenitor domains to OB interneuron diversity at CAGCGTATCC-3′)andRosa-tdTomato-3′ (5′-CTGTTC embryonic stages. CTGTACGGCATGG-3′) [37]. Zic3-lacZ BAC transgenic The normal generation and specification of OB inter- mice [38] were genotyped with the following primers: neurons are regulated by a number of transcription βgal5’ (5′-TGGGGAATGAATCAGGCCACGG-3′) and factors [7, 19]. For example, previous studies suggested βgal3’ (5′-GCGTGGGCGTATTCGCCAAGGA-3′). The that zinc finger transcription factor Sp8, which is Gsx1 knockout mice [39] and staged embryos were expressed by many post-mitotic neuroblasts from both genotyped with the following primers: Gsx1-WT1 Qin et al. Neural Development (2017) 12:13 Page 3 of 14 (5′-CGGGTGAAGCACAAGAAAGAAG-3′), Gsx1-WT2 field images were captured using an Olympus BX50 (5′-CCAATGGTCCTCTAAAAGGCG-3′), Gsx1-MT1 microscope. (5′-GGTTCATCATCACTAATCACGACG-3′)andGsx1- MT2 (5′-CGCTGTTCTCCCTCTTCCTCATCTC-3′). For embryonic analysis,
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